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  • 1
    Electronic Resource
    Electronic Resource
    Properties of isolated human islets of langerhans: insulin secretion, glucose oxidation and protein phosphorylation (1985)
    Springer
    Diabetologia 28 (1985), S. 99-103 
    Details
    ISSN: 1432-0428
    Keywords: Human islets ; insulin secretion ; glucose oxidation ; Ca2+-calmodulin ; protein kinases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In the present study, human islets were isolated by collagenase digestion from the pancreases of three kidney donors. Maintainance of the islets in tissue culture enabled insulin release, glucose oxidation and Ca2+-calmodulin-dependent protein phosphorylation to be determined using the same islets. Increasing glucose over a range 0–20 mmol/l resulted in a sigmoidal stimulation of insulin release (28.8±5.2 to 118.4±25.8 μU-islet−-h−, n=10; threshold 〈4 mmol/l). There was a marked correlation between the insulin secretory response of the islets to glucose and their rate of glucose oxidation (5.9±0.3 at glucose 2 mmol/l up to 25.8±1.8 pmol-islet−.h− at 20 mmol/l, r = 0.98). N-acetylglucosamine (20 mmol/l) failed to elicit a secretory response from the islets. Stimulation of insulin secretion by glucose was dependent upon the presence of extracellular Ca2+. Extracts of the islets contained a Ca2+-calmodulin-dependent protein kinase which phosphorylated a 48-kdalton endogenous polypeptide. Myosin light-chain kinase activity was demonstrated in the presence of exogenous myosin light chains. This report demonstrates for the first time the sigmoidal nature of glucose-stimulated insulin release from isolated human islets, and its correlation with enhanced glucose oxidation. Furthermore, this is the first report of the presence of Ca2+-dependent protein kinases in human islets.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00279924
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  • 2
    Electronic Resource
    Electronic Resource
    Insulin release from human pancreatic islets in vitro (1980)
    Springer
    Diabetologia 19 (1980), S. 114-117 
    Details
    ISSN: 1432-0428
    Keywords: Insulin secretion ; human islets of Langerhans ; pancreatic β-cell ; tissue culture
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Islets of Langerhans were isolated by collagenase digestion from the pancreas of a 39 year-old female renal transplant donor. The islets were subjected to three consecutive periods of tissue culture, after each of which they were incubated in vitro with various agents whose effects on insulin release from islets of laboratory animals have previously been established. After the first culture period, the basal insulin secretion rate of 5.2 μU/islet/h seen with 2 mmol/l glucose was increased approx. 5-fold on raising the glucose concentration to 20 mmol/l. The islets retained the insulin-secretory response to 20 mmol/l glucose throughout the period of study. Insulin secretion was also stimulated by mannose, leucine, α-ketoisocaproate, dihydroxyacetone and 3-hydroxybutyrate, but not by fructose or N-acetyl-glucosamine. Fructose however increased insulin release in the presence of 4 mmol/l glucose. Caffeine elicited insulin release in the absence of glucose and enhanced insulin release in response to 10 mmol/l glucose. Glucose-stimulated insulin release was inhibited by trifluoperazine (25 μmol/l).
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00421856
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  • 3
    Electronic Resource
    Electronic Resource
    Opioids, NSAIDs and 5-lipoxygenase inhibitors act synergistically in brain via arachidonic acid metabolism (1999)
    Springer
    Inflammation research 48 (1999), S. 1-4 
    Details
    ISSN: 1420-908X
    Keywords: Key words: Opioid — NSAID — 5-Lipoxygenase — Arachidonic acid — Pain
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. We have established that μ-opioid receptor activation causes a presynaptic inhibition of neurotransmitter release that is mediated by 12-lipoxygenase metabolites of arachidonic acid in midbrain neurons [1]. We further demonstrated that the efficacy of opioids was enhanced synergistically by treatment of brain neurons with inhibitors of the other major enzymes responsible for arachidonic acid metabolism; cyclooxygenase (COX-1) and 5-lipoxygenase. These findings explain a mechanism of analgesic action of NSAIDs in the central nervous system that is both independent of prostanoid release and inhibited by opioid antagonists, as well as the synergistic interaction of opioids with NSAIDs. These findings also suggest new avenues for development of centrally active medications involving combinations of lowered doses of opioids and specific 5-lipoxygenase inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s000110050367
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  • 4
    Electronic Resource
    Electronic Resource
    Protein phosphorylation in the pancreatic B-cell (1984)
    Springer
    Cellular and molecular life sciences 40 (1984), S. 1075-1084 
    Details
    ISSN: 1420-9071
    Keywords: Pancreatic B-cell ; protein phosphorylation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01971454
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  • 5
    Electronic Resource
    Electronic Resource
    Binding of antibodies in sera from Type 1 (insulin-dependent) diabetic patients to glutamate decarboxylase from rat tissues. Evidence for antigenic and non-antigenic forms of the enzyme (1992)
    Springer
    Diabetologia 35 (1992), S. 380-384 
    Details
    ISSN: 1432-0428
    Keywords: Autoantigens ; autoantibodies ; glutamic acid decarboxylase ; pancreatic islets
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary An islet protein of Mr 64000, identified as the γ-amino butyric acid (GABA)-synthesizing enzyme, glutamate decarboxylase, is a major target for antibodies in Type 1 (insulin-dependent) diabetes mellitus. This enzyme is also expressed in brain and in some other tissues and may exist in multiple forms. The aim of this study was to determine the ability of antibodies from diabetic patients to recognize glutamate decarboxylase from rat islets, brain and other normal rat tissues. Glutamate decarboxylase was detected at high activity levels in brain and at lower levels in islets, kidney, liver, pituitary gland, thyroid gland, adrenal gland, testis and ovary. The ability of antibodies in sera of diabetic patients to immunoprecipitate enzyme activity from detergent extracts of tissues was determined. Antibodies in sera from diabetic patients were found to bind the enzyme from islet and brain extracts, but bound less than 20% of the activity from other tissues. The ability of antibodies to immunoprecipitate the brain enzyme was significantly correlated with the presence of antibodies to the islet 64 kilodalton antigen. These studies show that the glutamate decarboxylase activity expressed in brain shares antigenic determinants with the islet 64 kilodalton antigen. Isoforms of the enzyme expressed in other nonneuronal tissues may be antigenically distinct and may lack determinants recognized by diabetes-associated antibodies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00401206
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  • 6
    Electronic Resource
    Electronic Resource
    Inflammatory islet damage in patients bearing HLA-DR 3 and/or DR 4 haplotypes does not lead to islet autoimmunity (1994)
    Springer
    Diabetologia 37 (1994), S. 471-475 
    Details
    ISSN: 1432-0428
    Keywords: Key words IDDM, chronic pancreatitis, islet cell antibodies, autoimmunity.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The hypothesis was tested that islet autoimmunity is induced by ongoing islet cell destruction in subjects with susceptibility genes HLA-DR 3 and/or DR 4. Sixty-one patients with confirmed chronic pancreatitis were analysed, 30 of whom expressed HLA-DR 3 and/or DR 4. Electron microscopy studies in 10 patients showed that the inflammatory process also affected islets, as recognisable from islet cell lysis, intrainsular fibrosis and immune cell infiltrates. None of the sera tested contained any of three markers of islet autoimmunity, ICA, IAA or GAD antibodies. A correlation was seen between the loss of exocrine function, as determined by the ALTAB-test, and of beta-cell function, as determined by the C-peptide response to i. v. glucagon. However, there was no preferential loss of beta-cell function in patients with HLA-DR 3 and/or DR 4. We conclude that islet cell destruction occurs during chronic pancreatitis, but does not trigger islet autoimmunity, even in the presence of HLA-DR 3 and/or DR 4. [Diabetologia (1994) 37: 471–475]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050134
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  • 7
    Electronic Resource
    Electronic Resource
    Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM (1997)
    Springer
    Diabetologia 40 (1997), S. 1327-1333 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Autoantibodies ; Autoantigens ; Tyrosine phosphatase ; Epitopes ; Insulin-dependent diabetes.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Patients with insulin-dependent diabetes mellitus (IDDM) possess antibodies to the cytoplasmic domains of two closely related tyrosine phosphatase-like proteins, IA-2 and phogrin, previously detected as 40 kDa and 37 kDa tryptic fragments, respectively. A higher proportion of IDDM patients possess antibodies to IA-2 than to phogrin, and autoimmunity to phogrin might arise through cross-reactivity with the highly homologous IA-2. In this study, we have investigated the major regions of IA-2 recognized by antibodies in IDDM patients and examined the ability of phogrin to block antibody binding to these regions as a measure of cross-reactivity. Analysis of antibody binding to in vitro transcribed and translated polypeptides representing different regions of the cytoplasmic domain of IA-2 identified five different patterns of reactivity with antibodies in IDDM. Protein footprinting analysis, whereby polypeptide fragments generated on protease treatment of immune complexes are studied, indicated considerable heterogeneity in antibody recognition of IA-2, even between sera with similar reactivity to deletion mutants. Blocking studies with recombinant phogrin indicated that IA-2 antibodies recognize epitopes that are both unique to IA-2 and shared with phogrin. The amino-terminal 150 amino acids of the cytoplasmic domain of IA-2 encompass epitopes that are not represented on phogrin, whereas shared epitopes are localized within the carboxy-terminal 220 amino acids. The results demonstrate considerable heterogeneity between IDDM patients in autoantibody recognition of IA-2 in IDDM, whereas antibody recognition of phogrin is restricted in most patients to epitopes also present on IA-2. [Diabetologia (1997) 40: 1327–1333]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050828
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  • 8
    Electronic Resource
    Electronic Resource
    IA-2-autoantibodies complement GAD65-autoantibodies in new-onset IDDM patients and help predict impending diabetes in their siblings (1997)
    Springer
    Diabetologia 40 (1997), S. 95-99 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin-dependent diabetes mellitus ; protein tyrosine phosphatases ; autoantibodies ; genetic susceptibility ; diabetes prediction.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary IA-2 has been identified as an autoantigen that is recognized by immunoglobulins from insulin-dependent diabetic (IDDM) patients. Using a liquid phase radiobinding assay, we performed an IA-2-autoantibody (IA-2-Ab) assay in 474 IDDM patients and 482 non-diabetic control subjects aged 0–39 years. IA-2-Ab were detected in 58 % of the patients and 0.8 % of control subjects. Their prevalence in patients was lower than that of islet cell autoantibodies (ICA; 73 %) or glutamic acid decarboxylase (Mr 65 kDa)-autoantibodies (GAD65-Ab; 82 %) but higher than that of insulin autoantibodies (IAA; 42 %). IA-2-Ab were more frequent in patients under age 20 years (70 %) than between 20 and 40 years (45 %; p 〈 0.001). In the whole IDDM group, 92 % of patients were positive for at least one of the three molecular assays, which is higher than the positivity for the ICA assay (73 %). Only 1 % was negative in the molecular assays and positive in the ICA assay. IA-2-Ab levels were positively correlated with ICA titres (p 〈 0.001) and HLA DQ A1*0301 – DQ B1*0302 (p 〈 0.003) by multivariate analysis. In a group of 481 non-diabetic siblings (age 0–39 years) of IDDM patients only 7 were IA-2-Ab positive (1.5 %). All seven were under age 20 years and positive for at least two other autoantibodies and for DQ A1*0301 – DQB1*0302. Four of these seven developed IDDM during the 6–70-month follow-up period. The positive predictive value of IA-2-Ab (57 %) was higher than that of ICA, GAD65-Ab or IAA alone, or in combination (≤ 20 %) but these calculations are restricted by the relatively short observation period and the small number of cases. The only IA-2-Ab-negative case of pre-diabetes was also negative for IAA and GAD65-Ab, while it was strongly positive for ICA. In conclusion, IA-2-Ab show a high diagnostic specificity for IDDM and are predictive markers of impending diabetes in siblings of patients. In combination with other molecular antibody assays they may replace ICA testing in future. Our data also indicate that other autoantibodies than IA-2-Ab, GAD65-Ab and IAA contribute to ICA. [Diabetologia (1997) 40: 95–99]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050648
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  • 9
    Electronic Resource
    Electronic Resource
    Combined screening for autoantibodies to IA-2 and antibodies to glutamic acid decarboxylase in first degree relatives of patients with IDDM (1996)
    Springer
    Diabetologia 39 (1996), S. 1351-1356 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Insulin-dependent diabetes mellitus ; antibodies to tyrosine phosphatase IA-2 ; GAD antibodies ; islet cell antibodies ; prediction.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary To determine the value of antibodies to the intracytoplasmic domain of the tyrosine phosphatase IA-2 (anti-IA-2 ic) and glutamic acid decarboxylase (GADA) for identification of subjects at risk for insulin-dependent diabetes mellitus (IDDM) we investigated 1238 first degree relatives of patients with IDDM for the presence of anti-IA-2 ic and GADA and compared the results with cytoplasmic islet cell antibodies (ICA). Anti-IA-2 ic were observed in 54 (4.4 %) first degree relatives, in 51 of 86 (59.3 %) ICA positive relatives and in 3 of 4 individuals who developed overt IDDM within a follow-up period of 1 to 28 months. GADA were found in 78 of 1238 (6.3 %) first degree relatives. They were detected in 22 of 35 (62.9 %) sera with ICA alone and in 1 of 3 subjects with anti-IA-2 ic in the absence of ICA. Of the 1238 subjects 37 (3.0 %) sera were positive for all three antibodies. Both anti-IA-2 ic and GADA were positively correlated with high levels of ICA. Anti-IA-2 ic and GADA were detected in 39.1 and 47.8 % of subjects with ICA of less than 20 Juvenile Diabetes Foundation units (JDF-U) but in 66.7 and 76.2 % of individuals with ICA of 20 JDF-U or more, respectively (p 〈 0.05). The levels of ICA and GADA in first degree relatives with at least one additional marker were significantly higher than in subjects with ICA alone (p 〈 0.005) or GADA alone (p 〈 0.03). The combination of anti-IA-2 ic and GADA identified 84.9 % of all ICA positive subjects and 93.7 % of individuals with high level ICA (≥ 20 IDF-U). All 4 individuals who progressed to IDDM had either IA-2 ic or GADA. Our data indicate that primary screening for anti-IA-2 ic and GADA provides a powerful approach with which to identify subjects at risk for IDDM in large-scale population studies which may represent the basis for the design of new intervention strategies. [Diabetologia (1996) 39: 1351–1356]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050582
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  • 10
    Electronic Resource
    Electronic Resource
    Slow metabolic deterioration towards diabetes in islet cell antibody positive patients with autoimmune polyendocrine disease (1994)
    Springer
    Diabetologia 37 (1994), S. 365-371 
    Details
    ISSN: 1432-0428
    Keywords: Key words Intravenous glucose tolerance test, 37 k-antibodies, islet cell antibody staining pattern, polyendocrinopathy.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We studied metabolic progression to IDDM in a cohort of adults who are ICA-positive and have associated autoimmune endocrine disease or circulating organ-specific autoantibodies (the Polyendocrine Study). Of the 186 individuals recruited 27 developed overt diabetes after a median follow-up of 4.5 years (range 0.4–12). Of these, eight patients did not require insulin treatment until at least 6 months after clinical diagnosis, with an interval of 1.8 years (1.2–5.7) . An IVGTT was performed in 38 subjects and 23 had sequential studies. Of the initial 38 subjects six developed diabetes and only three showed a loss of FPIR to glucose (below the first percentile of a normal control group) before clinical onset of the disease. An additional three subjects showed a loss of the FPIR, and all still have normal glucose tolerance after median follow-up of 28 months (22–95). A “whole” or “mixed” pattern of islet cell staining was found in five of the six patients who developed diabetes and antibodies against an islet 37 k-antigen were detectable in four patients, all of whom required insulin soon after diagnosis. A beta-cell “selective” ICA staining pattern was seen in 14 of 17 subjects who did not develop diabetes and the “mixed” pattern in only three. None of this group had detectable 37 k-antibodies. We conclude that metabolic deterioration is slow in polyendocrine patients, and that the IVGTT has less prognostic significance in this group than in first degree relatives of patients with IDDM. In contrast, the presence of the “whole” or “mixed” ICA staining pattern or of 37 k-antibodies can identify a high risk of progression to IDDM within this polyendocrine population and may indicate the rate of metabolic deterioration. [Diabetologia (1994) 37: 365–371]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00408472
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